Amyloid fiber formation limiter or inhibitor

ABSTRACT

The object of the present invention is to provide a formulation with the effect of effectively suppressing or inhibiting amyloid fibril formation by the dissolution, elimination (discharge), etc. of amyloid fibril formation in vivo. 
     If an agent for suppressing or inhibiting an amyloid fibril formation comprising tranilast or a pharmacologically acceptable salt thereof as an active ingredient is administered by a method such as oral administration, amyloid fibril formation can be effectively suppressed or inhibited in vivo as a result of effects such as amyloid fibril dissolution or elimination (discharge). Therefore, it is possible to prevent or treat amyloid plaques, in which amyloid fibrils formed by the aggregation of amyloid protein have been deposited, and to prevent or treat diseases arising from amyloid fibril deposition, that is, diseases arising from the deposited amyloid fibrils themselves and diseases that cause dysfunction of organs or tissues as a result of amyloid fibril deposition.

TECHNICAL FIELD

The present invention relates to a formulation for suppressing orinhibiting an amyloid fibril formation with the effect of dissolving oreliminating (discharging) amyloid fibrils, comprising tranilast or apharmacologically acceptable salt thereof as an active ingredient, to anagent for preventing or treating an amyloid plaque comprising saidformulation, or to an agent for preventing or treating amyloidosiscomprising said formulation.

BACKGROUND ART

Amyloid fibril is a fibrous supramolecular polymer formed by theaggregation of misfolded proteins. Pathologically, amyloid fibrils arestained orange-red with alkaline Congo red staining, show greenbirefringence in the observation using a polarizing microscope, and showan unbranched fibrous structure with a width of 7 to 15 nm in theobservation using an electronic microscope.

Amyloidosis is a collective term for the diseases that cause dysfunctiondue to amyloid fibril deposition in organs or tissues that workscontinuously or in organs or tissues that are affected with adebilitating disease. In 1980, Glenner, G. C. showed that proteins(amyloid protein) constituting amyloid fibrils that are specific to eachdisease form amyloid fibrils abundant with a β-sheet structure and causea deposition, and thereafter, there has been a variety of reports on theassociation between amyloid proteins and diseases. For example, anassociation between an amyloid fibril composed of amyloid β and diseasessuch as Alzheimer's type senility, Down syndrome; an association betweenan amyloid fibril composed of α-synuclein and diseases such asParkinson's disease, Lewy body type senility, multiple system atrophy;an association between an amyloid fibril composed of prion and diseasessuch as Creutzfeldt-Jakob disease, Gerstmann-Sträussler syndrome, madcow disease; and an association between an amyloid fibril composed oftau and diseases such as Alzheimer's type senility, FTDP-17, progressivesupranuclear palsy, corticobasal degeneration, Pick's disease have beenreported (Non-Patent Document 1).

It is believed that, besides amyloid fibril deposition itself,intermediate molecules such as oligomers or protofibrils, which areinvolved in amyloid fibril formation, are one of the causes of celldeath or cellular disorder (Non-Patent Documents 2, 3). Therefore, it isbelieved that amyloidosis can be treated by suppressing amyloid fibrilformation to increase the instability of the proteins constitutingamyloid fibrils (Non-Patent Document 4).

Until now, clioquinol (Patent Document 1), curcumin (Non-Patent Document5), tannic acid (Non-Patent Document 6), hemin (Non-Patent Document 7),melatonin (Non-Patent Document 8), 4,5-dianilinophthalimide (Non-PatentDocument 9), L-DOPA (Non-Patent Document 10),hexadecyl-N-methylpiperidinium (Non-Patent Document 11), congo red,which is a fluorescent stain (Non-Patent Document 12), etc. have beenreported as compounds for suppressing amyloid fibril formation.

On the other hand, tranilast is a compound that has already beencommercially supplied form Kissei Pharmaceutical Co., Ltd. as anantiallergic drug “Rizaben”, and has been reported as showing good drugefficacy against keloid, hypertrophic scar (Non-Patent Documents 13,14). However, it has not been known whether tranilast has an effect ofsuppressing amyloid fibril formation.

PRIOR ART DOCUMENTS Patent Documents

Patent Document 1: WO 98/06403

Non-Patent Documents

Non-Patent Document 1: Chiti, F. & Dobson, C. M. Nat. Chem. Biol. 5:15-22 (2009)

Non-Patent Document 2: Kayed, R. et al., Science 300: 486-489 (2003)

Non-Patent Document 3: Tsai, J. et al., Nature Neuroscience 7: 1181-1183(2004)

Non-Patent Document 4: Hammarstrom, P., Science 293: 2459-2462 (2001)

Non-Patent Document 5: Ono, K. et al., J. Neurosci. Res. 75: 742-750(2004)

Non-Patent Document 6: Ono, K. et al., Biochim. Biophys. Acta, 1690:193-202 (2004)

Non-Patent Document 7: Howlett, D. R. et al., FEBS Lett. 417: 249-251(1997)

Non-Patent Document 8: Pappolla, M. et al., J. Biol. Chem. 273:7185-7188 (1998)

Non-Patent Document 9: Blanchard, B. et al., Proc. Natl. Acad. Sci. USA.101: 14326-14332 (2004)

Non-Patent Document 10: Li, J. et al., FASEB J. 18: 962-964 (2004)

Non-Patent Document 11: Wood, S. et al., J. Biol. Chem. 271: 4086-4092(1996)

Non-Patent Document 12: Lorenzo, A. & Yankner, B. A., Proc. Natl. Acad.Sci. USA. 91: 12243-12247 (2004)

Non-Patent Document 13: Ichikawa K. et al., Ohyoyakuri(Pharmacometrics): 43(5) 401 (1992)

Non-Patent Document 14: Suzawa H., NihonYakurigakuZasshi (FoliaPharmacologica Japonica): 99(4) 231 (1992)

SUMMARY OF THE INVENTION Object to be Solved by the Invention

The object of the present invention is to provide a formulation with theeffect of effectively suppressing or inhibiting amyloid fibril formationby the dissolution or elimination (discharge), etc. of an amyloid fibrilin vivo.

Means to Solve the Object

The present inventor has been extensively investigating to solve theabove-described problems. During the process, it was investigatedwhether amyloid deposition in the skin could be reduced or whethercutaneous lichen amyloidosis could be treated by using tranilast (brandname: Rizaben) known as a therapeutic agent for atopic dermatitis, andit was found that the amyloid fibril formation was suppressed and thefunction of skin could be improved upon the administration of tranilast.Further, based on the finding, it was investigated whether dementiaarising from amyloid fibril deposition could be ameliorated and it wasconfirmed that clear ameliorating effect was observed upon theadministration of tranilast. The present invention has been thuscompleted based on these findings.

Specifically, the present invention relates to (1) an agent forsuppressing or inhibiting an amyloid fibril formation, comprisingtranilast or a pharmacologically acceptable salt thereof as an activeingredient, (2) the agent according to (1), wherein the agent isadministered orally, (3) the agent according to (1) or (2), wherein theagent has an effect of dissolving or discharging an amyloid fibril.

Further, the present invention relates to (4) an agent for preventing ortreating an amyloid plaque, comprising the agent according to any one of(1)-(3), (5) the agent according to (4), wherein the amyloid plaque isin the brain, (6) the agent according to (4), wherein the amyloid plaqueis in the skin.

Further, the present invention relates to (7) an agent for preventing ortreating an amyloidosis, wherein the agent comprises the agent accordingto any one of (1)-(3), (8) the agent according to (7), wherein theamyloidosis is cerebral amyloidosis, (9) the agent according to (8),wherein the cerebral amyloidosis is dementia arising from the depositionof an amyloid fibril in the brain, (10) the agent according to (7),wherein the amyloidosis is cutaneous amyloidosis, (11) the agentaccording to (10), wherein the cutaneous amyloidosis is cutaneous lichenamyloidosis.

Examples of still another embodiment of the present invention caninclude a method for preventing or treating amyloid plaques or a methodfor preventing or treating diseases arising from amyloid fibrildeposition (diseases arising from the deposited amyloid fibrilsthemselves and diseases that cause dysfunction of organs or tissues as aresult of amyloid fibril deposition), by administering an agent forsuppressing or inhibiting an amyloid fibril formation comprisingtranilast or a pharmacologically acceptable salt thereof as an activeingredient to a patient in need of suppressing or inhibiting of amyloidfibril formation.

Examples of still another embodiment of the present invention caninclude tranilast or a pharmacologically acceptable salt thereof for useas an agent for suppressing or inhibiting an amyloid fibril formation,tranilast or a pharmacologically acceptable salt thereof for use as anagent for preventing or treating an amyloid plaque, or tranilast or apharmacologically acceptable salt thereof for use as an agent forpreventing or treating an amyloidosis.

Examples of still another embodiment of the present invention caninclude the use of tranilast or a pharmacologically acceptable saltthereof in the manufacture of an agent for suppressing or inhibiting anamyloid fibril formation, the use of tranilast or a pharmacologicallyacceptable salt thereof in the manufacture of an agent for preventing ortreating an amyloid plaque, or the use of tranilast or apharmacologically acceptable salt thereof in the manufacture of an agentfor preventing or treating amyloidosis.

Effect of the Invention

According to the present invention, amyloid fibril formation can beeffectively suppressed or inhibited in vivo by the effects such asamyloid fibril dissolution or elimination (discharge). Therefore, it ispossible to prevent or treat amyloid plaques, and to prevent or treatdiseases arising from amyloid fibril deposition (diseases arising fromthe deposited amyloid fibrils themselves and diseases that causedysfunction of organs or tissues as a result of amyloid fibrildeposition).

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a figure showing improvement in symptoms achieved byadministering tranilast to a patient with cutaneous lichen amyloidosis(Case 2).

FIG. 2 is a figure showing improvement in symptoms achieved byadministering tranilast to a patient with cutaneous lichen amyloidosis(Case 3).

MODE OF CARRYING OUT THE INVENTION

The agent for suppressing or inhibiting an amyloid fibril formation ofthe present invention comprises tranilast or a pharmacologicallyacceptable salt thereof (hereinafter referred to collectively as“tranilasts”) as an active ingredient, and, if necessary, compoundingingredients can further be added, such as a pharmaceutically acceptablecommon carrier, a binder, a stabilizer, an excipient, a diluent, a pHbuffering agent, a disintegrator, an isotonic agent, an additive, acoating, a solubilizer, a lubricating agent, a sliding agent, asolubilizing agent, a lubricant, a seasoning, a sweetening agent, asolvent, a gelatinizer, and a nutrient. Specific examples of suchcompounding ingredients can include water, physiological saline, animalfat and oil, vegetable oil, lactose, starch, gelatin, crystallinecellulose, gum, talc, magnesium stearate, hydroxypropylcellulose,polyalkylene glycol, polyvinyl alcohol, and glycerin.

The agent for suppressing or inhibiting an amyloid fibril formation ofthe present invention has an effect of suppressing or inhibiting amyloidfibril formation in vivo. The effect of suppressing or inhibitingamyloid fibril formation in vivo can include for example, in cells ortissues in which amyloid fibrils have been deposited, an effect ofsuppressing the production of a protein constituting an amyloid fibril(amyloid protein), an effect of suppressing the aggregation of anamyloid protein, an effect of degradation of an amyloid protein, aneffect of dissolving (degradation of) an amyloid fibril (structure), andan effect of discharging an amyloid protein or an amyloid fibril to theoutside of said cells or tissues. The effect of dissolution(degradation) of an amyloid fibril (structure) and the effect ofdischarging an amyloid protein or an amyloid fibril to the outside ofsaid cells or tissues are preferable.

In the present invention, “amyloid fibril” refers to a fibroussupramolecular polymer formed by the aggregation of misfolded(high-ordered-structure abnormally formed) proteins (amyloid protein)and has the structure which is abundant with a β-sheet. Examples of theabove-described amyloid protein can include proteins such as amyloid β,tau, immunoglobulin light chain, amylin, amyloid A, transthyretin,lysozyme, BriL, cystatin C, scrapie, β2 microglobulin, apolipoproteinA1, gelsolin, islet amyloid, fibrinogen, prolactin, insulin, calcitonin,keratin, atrial natriuretic peptide, α-synuclein, prion, huntingtin,superoxide dismutase, neuroserpin, α1-antichymotrypsin.

Tranilast of the present invention isN-(3,4-dimethoxycinnamoyl)anthranilic acid and is a compound representedby the chemical structural formula shown below.

Examples of pharmacologically acceptable salt of tranilast of thepresent invention include a metal salt formed from aluminium, calcium,lithium, magnesium, potassium, sodium, and zinc, and an organic saltformed from N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methylglucamine, lysine, procaine,etc.

The agent for preventing or treating an amyloid plaque of the presentinvention and the agent for preventing or treating an amyloidosis of thepresent invention are not particularly limited as long as they comprisean agent for suppressing or inhibiting an amyloid fibril formation ofthe present invention, that is, as long as they comprise tranilasts asan active ingredient for the effect of suppressing or inhibiting amyloidfibril formation, and examples include those further added withcompounding ingredients such as a pharmaceutically acceptable commoncarrier, a binder, a stabilizer, an excipient, a diluent, a pH bufferingagent, a disintegrator, an isotonic agent, an additive, a coating, asolubilizer, a lubricating agent, a sliding agent, a solubilizing agent,a lubricant, a seasoning, a sweetening agent, a solvent, a gelatinizer,and a nutrient. Specific examples of such compounding ingredients caninclude water, physiological saline, animal fat and oil, vegetable oil,lactose, starch, gelatin, crystalline cellulose, gum, talc, magnesiumstearate, hydroxypropylcellulose, polyalkylene glycol, polyvinylalcohol, and glycerin.

Examples of the dosage form of the agent for suppressing or inhibitingan amyloid fibril formation of the present invention, of the agent forpreventing or treating an amyloid plaque of the present invention, andof the agent for preventing or treating an amyloidosis of the presentinvention can include oral administration in drug forms such as powder,granule, tablet, capsule, syrup, or suspension, and parenteraladministration including injection in a drug form such as solution,emulsion, or suspension, administration in a drug form of transdermalagent to the skin, administration to the eyes in a drug form of eyedrops, or nasal administration in a drug form such as nasal drops, nasalsprays, and oral administration is preferable.

The dosage of tranilasts in the agent for suppressing or inhibiting anamyloid fibril formation of the present invention, tranilasts in theagent for preventing or treating an amyloid plaque of the presentinvention, and tranilasts in the agent for preventing or treating anamyloidosis of the present invention is determined as appropriatedepending on age, body weight, gender, symptom, susceptibility to drug,etc. Usually, the agent is administered in a dosage range of 1 mg to 30g/day, preferably in a dosage range of 10 to 3000 mg/day, morepreferably in a dosage range of 50 to 2000 mg/day, still preferably in adosage range of 100 to 1000 mg/day, still more preferably in a dosagerange of 200 to 600 mg/day, once or more than once (e.g., two to fourtimes) in divided doses per day, however, the dosage may be adjusteddepending on the state of symptom improvement. Tranilasts, that are theactive ingredient of the present invention, are a drug (brand name:Rizaben [RIZABEN]) that has already been used for patients with atopicdermatitis, and the usage and the side effects thereof are well known.Therefore, the dosage and the dosage form can be selected based onexperiences when using the agent for suppressing or inhibiting anamyloid fibril formation of the present invention, the agent forpreventing or treating an amyloid plaque of the present invention, andthe agent for preventing or treating an amyloidosis of the presentinvention.

An amyloid fibril that is the application for the agent for suppressingor inhibiting an amyloid fibril formation of the present invention isnot particularly limited as long as it is an amyloid fibril formed inorgans or tissues; further, an amyloid plaque that is the applicationfor the agent for preventing or treating an amyloid plaque of thepresent invention is not particularly limited as long as it is anamyloid plaque in which amyloid fibrils formed by the aggregation ofamyloid protein in organs or tissues have been deposited; further,amyloidosis that is the application for the agent for preventing ortreating an amyloidosis of the present invention is not particularlylimited as long as it is a disease arising from amyloid fibrildeposition (diseases arising from deopsited amyloid fibrils themselvesand diseases that cause dysfunction of organs or tissues as a result ofamyloid fibril deposition); wherein examples of the organs or tissuescan include brain, lung, liver, kidney, heart, intestine (largeintestine, small intestine, colon, etc.), pancreas, bone (bone marrow),skin, etc. and among these brain or skin can be preferably exemplified.

Any method may be used for detecting amyloid plaques. For example, ofamyloid plaques in the brain, the amyloid plaques composed of amyloid β(senile plaques) can be detected by a method using ¹¹C labeled PIB(Pittsburgh Compound-B) deposited in said part (Japanese UnexaminedPatent Application Publication (Translation of PCT Application) No.2004-506723) and a device (PET-CT) for investigations by PositronEmission Tomography (PET; Positron Emission Tomography) and ComputerizedTomography (CT; Computerized Tomography) simultaneously. Further,amyloid plaques in the skin can be detected as punctate brown pigmentedspots formed in crista cutis (a raised portion between skin grooves)except follicle. Here, said punctate brown pigmented spot ischaracteristic in that the punctate pigmented spots with a diameter of 2to 3 mm are linearly arranged, and that looks ripplelike arrangement.

Examples of the above-described amyloidosis can include, specifically,systemic amyloidosis such as immune cellular amyloidosis (e.g., ALamyloidosis, AH amyloidosis), reactive AA amyloidosis (secondaryamyloidosis), familial amyloidosis (e.g., Familial AmyloidPolyneuropathy [FAP] I, FAPII, FAPIII, FAPIV, Familial Mediterraneanfever [FMF], Muckle-Wells syndrome), dialysis amyloidosis, senile TTRamyloidosis, and localised amyloidosis such as cerebral amyloidosis,endocrine amyloidosis (medullary thyroid cancer, diabetes mellitus type2, insulinoma, isolated atrial amyloid), cutaneous amyloidosis, nodularlocalised amyloidosis, and among these cerebral amyloidosis or cutaneousamyloidosis can be preferably exemplified.

Examples of the above-described cerebral amyloidosis can include,specifically, cerebral amyloid angiopathy, hereditary cerebralhemorrhage (Dutch type or Icelandic type) arising from amyloid fibrildeposition in the brain, and dementia arising from amyloid fibrildeposition in the brain, and among these dementia arising from amyloidfibril deposition in the brain can be preferably exemplified. Said“dementia” can be exemplified by Alzheimer's type dementia (senility),dementia developed from Parkinson's disease, dementia developed fromDown syndrome, dementia developed from prion diseases, Lewy bodies typedementia (senility), dementia developed from multiple system atrophy,dementia developed from Creutzfeldt-Jakob disease, dementia developedfrom Gerstmann-Sträussler syndrome, dementia developed from mad cowdisease, dementia developed from FTDP-17, dementia developed fromprogressive supranuclear palsy, dementia developed from corticobasaldegeneration, and dementia developed from Pick's disease.

Further, examples of the above-described cutaneous amyloidosis caninclude, specifically, friction melanosis, lichen (cutaneous lichenamyloidosis), macular (cutaneous macular amyloidosis), and anosacralcutaneous (anosacral cutaneous amyloidosis) arising from amyloid fibrildeposition in the skin, and among these cutaneous lichen amyloidosis canbe preferably exemplified.

The above-described tranilasts can be produced by any publicly knownmethods such as chemical synthesis, production by microorganisms,production by enzyme, however, commercially marketed products may alsobe employed. For example, commercially marketed products such as Rizabencapsule, Rizaben granules, Rizaben dry syrup (all from KisseiPharmaceutical Co., Ltd.), Ainteru capsule 100 mg, Ainteru dry syrup(all from Choseido Pharmaceutical Co., Ltd.) are included.

The present invention is illustrated in detail with the followingexamples, however, the present invention is not limited to theseexamples.

EXAMPLE 1 1. Confirmation That the Agent for Suppressing or Inhibitingan Amyloid Fibril Formation of the Present Invention has a TherapeuticEffect Against Cutaneous Amyloidosis 1-1 Case 1

A patient (N.Y, 60 years of age, female) observed with symptoms ofcutaneous amyloidosis specific pigment-associating invasion and itch inthe upper back had been treated without tranilast for an initialduration of 4 years, however, no therapeutic effect was observed.Therefore, the treatment shifted to the use of tranilast. Theabove-mentioned patient was administered orally with a 100 mg capsule oftranilast (brand name: Rizaben, Kissei Pharmaceutical Co., Ltd.) threetimes a day. About 1 month after the start of oral administration thepigmentation started to thin, and within another 1 month it was shownthat itch was reduced and rash was largely ameliorated, with the gradualreduction of the level of pigmentation. Worsening or relapse of rash wasnot observed at least 3 years afterwards.

1-2 Case 2

A patient observed with symptoms of typical amyloid lichen in the upperback (27 years of age, female, atopic dermatitis appeared in early life)was at first under treatment with difluprednate ointment (MYSEROintment), which is a topical steroid categorized into “Very Strong:group II”, however, amelioration was not observed. Therefore, thetreatment shifted to the use of tranilast. The above-mentioned patientwas administered orally with a 100 mg capsule of tranilast (brand name:Rizaben, Kissei Pharmaceutical Co., Ltd.) three times a day. From day 16(Jul. 16, 2014) (see FIG. 1B) after the start of oral administration onJun. 30, 2014 (see FIG. 1A), amyloid deposited brown papule was found tobe thinned, decreased in size, and ameliorated clearly. The degree ofamelioration of rash increased day by day (see FIGS. 1C to E). Amyloiddeposited brown papule almost disappeared on day 151 (Nov. 28, 2014)(see FIG. 1F) after the start of oral administration, and the conditionwas maintained until at least day 238 (Feb. 23, 2015) (see FIG. 1H).

1-3 Case 3

A patient (23 years of age, female) observed with chronic eczema withrash along with strong itch in the upper back for several years startedthe treatment with tranilast. The patient was administered orally with a100 mg capsule of tranilast (brand name: Rizaben, Kissei PharmaceuticalCo., Ltd.) three times a day. When the oral administration started onJul. 29, 2014, amyloid deposited brown papule was densely lichenified(see FIG. 2A). However, on day 15 (Aug. 13, 2014) (see FIG. 2B) afterthe start of oral administration, improvement in the symptoms wasobserved. Further, on day 29 (Aug. 27, 2014) (see FIG. 2C) after thestart of oral administration, clear improvement in the symptoms wasobserved, and the improved condition was maintained afterwards until atleast day 89 (Oct. 26, 2014) (see FIGS. 2D to G).

These results show that, in skin tissues or cells in which amyloidfibrils have been deposited, tranilast suppressed or inhibited amyloidfibril formation in skin tissues or cells and improved the function ofthe skin by suppressing the production of amyloid proteins such askeratin, by suppressing the aggregation of amyloid protein, by promotingthe dissolution (degradation) of amyloid protein, or by promoting thedischarge of amyloid protein to the outside of skin tissues or cells.

EXAMPLE 2 2. Confirmation That the Agent for Suppressing or Inhibitingan Amyloid Fibril Formation of the Present Invention has a TherapeuticEffect Against Cerebral Amyloidosis

Because it was shown that tranilast has the effect of suppressingamyloid fibril formation in the skin, whether dementia and Alzheimer'sdisease arising from amyloid fibril deposition in the brain could beameliorated was studied.

2-1 Case 4

A patient with dementia (H.Y, 79 years of age, male) was administeredorally with a 100 mg capsule of tranilast (brand name: Rizaben, KisseiPharmaceutical Co., Ltd.) three times a day. 1 year and 4 months afterthe start of administration of tranilast in August 2012, clearameliorating effect was observed (see Table 1) by two types of testingmethods for dementia (HDS-R [Hasegawa Dementia Scale—Revised] and MMSE[Mini-Mental State Examination]).

TABLE 1 Start of Tranilast Administration HDS-R Value MMSE Value 3 yearsand 10 months before — 28 (October 2008) 1 year and 5 months before 2327 (March 2011) start of the administration — — (August 2012) 5 monthsafter 15 22 (January 2013) 1 year and 4 months after 20 25 (December2013)

2-2 Case 5

A patient with Alzheimer' s disease (88 years of age, male) wasadministered orally with a 100 mg capsule of tranilast (brand name:Rizaben, Kissei Pharmaceutical Co., Ltd.) three times a day. About 5months after the start of administration of tranilast on Oct. 11, 2014,clear ameliorating effect on the symptoms of Alzheimer's type dementiawas observed (see Table 2) by two types of testing methods for dementia(HDS-R and MMSE).

TABLE 2 Start of Tranilast Administration HDS-R Value MMSE Value startof the administration 9 14 (Oct. 11, 2014) about 5 months after 12 22(Mar. 19, 2015)

These results show that, in nerve tissues or cells in which amyloidfibrils have been deposited, tranilast suppressed or inhibited amyloidfibril formation in the nerve tissues or cells and improved the nervefunction, by suppressing the production of amyloid proteins such asamyloid β, by suppressing the aggregation of amyloid proteins, bypromoting the dissolution (break-down) of amyloid proteins, or bypromoting the discharge of amyloid proteins to the outside of the nervetissues or cells.

3. Summary

It has been known conventionally that if a certain tissue is chronicallyin a debilitating condition over long periods; for example, one suffersfrom a debilitating disease such as atopic dermatitis over long periods,amyloid fibrils deposit in the skin and refractory cutaneous lichenamyloidosis is caused. It is considered that tranilast acted such thatit would effectively reduce the deposited amyloid fibrils in the skin orbrain tissues in the hippocampus upon the systemic administration oftranilast to a patient with cutaneous lichen amyloidosis or a patientwith dementia such as Alzheimer's type dementia with no improvement ofsymptoms observed with conventional treatments. That is, the treatmentwith tranilast is effective also in brain tissues and therefore it isconsidered that tranilast passed the blood-brain barrier.

INDUSTRIAL APPLICABILITY

The present invention can effectively suppress or inhibit amyloid fibrilformation in vivo as a result of effects of tranilast, such as amyloidfibril dissolution or elimination (discharge). Therefore, the presentinvention is effective to prevent or treat amyloid plaques, and toprevent or treat diseases arising from amyloid fibril deposition(diseases arising from the deposited amyloid fibrils themselves anddiseases that cause dysfunction of organs or tissues as a result ofamyloid fibril deposition).

1-11. (canceled)
 12. A method for suppressing or inhibiting an amyloidfibril formation comprising administering an agent for suppressing orinhibiting an amyloid fibril formation to a patient in need ofsuppressing or inhibiting an amyloid fibril formation, wherein the agentcomprises tranilast or a pharmacologically acceptable salt thereof as anactive ingredient.
 13. The method according to claim 12, wherein theagent is administered orally.
 14. The method according to claim 12,wherein the agent has an effect of dissolving or discharging an amyloidfibril.
 15. A method for preventing or treating an amyloid plaquecomprising administering an agent for suppresing or inhibiting anamyloid fibril formation to a patient in need of preventing or treatingan amyloid plaque, wherein the agent comprises tranilast or apharmacologically acceptable salt thereof as an active ingredient. 16.The method according to claim 15, wherein the agent is administeredorally.
 17. The method according to claim 15, wherein the agent has aneffect of dissolving or discharging an amyloid fibril.
 18. The methodaccording to claim 15, wherein the amyloid plaque is in the brain. 19.The method according to claim 16, wherein the amyloid plaque is in thebrain.
 20. The method according to claim 15, wherein the amyloid plaqueis in the skin.
 21. The method according to claim 16, wherein theamyloid plaque is in the skin.
 22. A method for preventing or treatingan amyloidosis comprising administering an agent for suppressing orinhibiting an amyloid fibril formation to a patient in need ofpreventing or treating an amyloidosis, wherein the agent comprisestranilast or a pharmacologically acceptable salt thereof as an activeingredient.
 23. The method according to claim 22, wherein the agent isadministered orally.
 24. The method according to claim 22, wherein theagent has an effect of dissolving or discharging an amyloid fibril. 25.The method according to claim 22, wherein the amyloidosis is cerebralamyloidosis.
 26. The method according to claim 25, wherein the cerebralamyloidosis is dementia arising from the deposition of an amyloid fibrilin the brain.
 27. The method according to claim 23, wherein theamyloidosis is cerebral amyloidosis.
 28. The method according to claim27, wherein the cerebral amyloidosis is dementia arising from thedeposition of an amyloid fibril in the brain.
 29. The method accordingto claim 22, wherein the amyloidosis is cutaneous amyloidosis.
 30. Themethod according to claim 29, wherein the cutaneous amyloidosis iscutaneous lichen amyloidosis.
 31. The method according to claim 23,wherein the amyloidosis is cutaneous amyloidosis.